Abstract In young healthy individuals minor insults to bone heal with minimal compromise. In an aging population, in chronic disease, and with large reconstructive needs, the process often fails leaving compromised form and function. Work in the previous project period as well as work from others has identified actions of the anabolic agent parathyroid hormone (PTH) to drive osteoclastogenesis and localization of macrophages on the endosteal surface. Such osteal macrophages are essential for normal osseous healing where they act to increase bone formation through various mechanisms. A vital function of macrophages is in the clearance of dead and dying cells, a process termed efferocytosis. Upon efferocytosis, macrophages produce factors which facilitate resolution and regeneration. Based on findings of cellular actions of calcium and drug delivery modalities in the previous funding period, the project team proposes a new strategy for bone regeneration. Biomimicry based on developing calcium loaded biodegradable microspheres with surface signals that macrophages recognize as dying cells triggers efferocytosis and the secretion of factors to evoke wound healing. The overall hypothesis of this proposal is that apoptotic cell mimicry enhances bone regeneration via macrophage efferocytosis. Three aims will dissect the mechanisms involved, optimize microsphere properties, and translate to clinically relevant models that will move this novel approach forward. Specifically, aim one will utilize apoptotic mimicry microspheres to elucidate the role of the macrophage derived chemokine CCL2 in mesenchymal stem cell (MSC) migration and osteogenesis. Aim two will develop optimal apoptosis-mimicry microspheres to drive MSC migration by modulating the size, composition, and surface signals. Aim three will determine the osseous regenerative capacity of calcium loaded apoptotic cell mimicry microspheres using a clinically relevant animal model. At the completion of this project, a new strategy that does not require cell transplantation but builds upon the innate capacity of macrophages to regenerate bone will be mechanistically validated, characterized and optimized for translation to a clinical application.